Project Summary Sulfur dioxide (SO2) has been recognized as a potential signaling molecule in cardiovascular systems. Although SO2's exact mechanisms of action are still under investigation, the production of endogenous SO2 and the exogenous administration of SO2 have been demonstrated to exert protective effects in models of certain cardiovascular diseases. These results strongly suggest that modulation of SO2 levels could have potential therapeutic values. In this field, suitable SO2 releasing agents (i.e. donors) are important research tools for better understanding the roles of SO2 in cardiovascular systems. The donors are also potential therapeutic agents. Unfortunately, only very few SO2 donors are currently known. Moreover, these compounds are not ideal for biological studies due to their bio-incompatible SO2 release mechanisms. This represents a significant limitation for fundamental SO2 studies, as well as for the use of SO2 therapy in chronic cardiovascular and other disease states. Our recent study revealed that benzothiazole sulfinate (BTS) is a suitable template for the design of novel SO2 donors. In this project, our goal is to develop and optimize long-lasting and controllable SO2 donor based on BTS and related structures. We will also explore cardioprotective actions of the donors in cell models of myocardial ischemia/reperfusion (MI/R) injury. We expect promising candidates will be identified for future evaluations in animal models of MI/R and heart failure.